Testosterone Gel Trial Ends After Heart Issue

By RONI CARYN RABIN

Published: July 6, 2010

A federally financed study to see if testosterone gel helps frail elderly men build muscle and strength was abruptly halted late last year after participants taking it suffered a disproportionate number of heart attacks and other serious cardiac problems, and one died of what was apparently a heart attack.

Ten men taking testosterone suffered serious cardiac problems, compared with only one in a control group of elderly men who were applying a fake placebo gel, according to a paper published in The New England Journal of Medicine. The journal disclosed details of the trial's premature termination for the first time last week.

Researchers were taken aback by the high rate of adverse heart problems. Some experts called it an anomaly, and pointed to the fact that the trial's participants were sicker than patients in earlier testosterone studies and were treated with a relatively high dose of the hormone. Still, investigators about to begin a much larger set of testosterone trials immediately modified their study protocols, developing new inclusion criteria and agreeing to additional safety monitoring steps.

''There was a great deal of consternation and deliberation,'' said Dr. Shalender Bhasin, a professor at Boston University School of Medicine and the senior author on the paper about the trial. ''The lesson to be learned here is that physicians and patients, especially older men who are considering testosterone therapy, should weigh these findings of adverse events in their decision making.''

Dr. Evan Hadley, director of the division of geriatrics and clinical gerontology at the National Institute on Aging, which financed the study, said it would continue to study the hormone's effects. ''It's important to look at all the evidence about testosterone treatment,'' Dr. Hadley said. ''Other studies in older men haven't seen this pattern.''

Testosterone is not approved for use in older men whose testosterone levels have declined with age. The Food and Drug Administration has approved it for use only in men with hypogonadism, whose sex glands produce extremely low amounts of testosterone or none at all because of an underlying disorder. But the use of testosterone for other purposes, known as off-label use, has increased in recent years, with many older men taking it because of a belief it can counter or reverse the effects of aging.

There is very little solid evidence from randomized clinical trials about the potential benefits of testosterone treatment for these men. There are also concerns about long-term use, like the possibility that higher hormone levels could increase the risk of prostate cancer. The new clinical trials being financed by the National Institute on Aging are an effort to fill the information gap.

Participants in the trial that was stopped prematurely, called the Testosterone in Older Men With Mobility Limitations, or TOM, were non-institutionalized men aged 65 and older who had difficulty walking two blocks or climbing 10 steps and whose serum testosterone was 100 to 350 nanograms per deciliter (the normal range is 300 to 1,200 nanograms per deciliter). The goal was to recruit 252 men, but only 209 subjects had been enrolled by the time the trial, which started in 2005, was stopped last Dec. 31. Testosterone use had the desired effect of improving the men's muscle strength and mobility. But they also experienced a high rate of adverse effects -- not just cardiovascular problems but respiratory and skin problems.

Dr. Peter J. Snyder of the University of Pennsylvania School of Medicine is leading a much larger $45 million study financed by the N.I.A. In the 12-center trial, 800 men 65 and older who have low testosterone will be randomly assigned to testosterone treatment or placebo for a year. The trial, which is actually a set of studies, will assess testosterone's effect on physical functioning, fatigue and sexual and cognitive function. ''There is even a cardiovascular trial, the hypothesis of which is that testosterone actually makes cardiac risk factors better,'' said Dr. Snyder, who characterized the TOM results as an aberration.